·To describe Laplace´s law, the law of conservation of matter for determination of volume
and flow, the Starling equation, net filtration with lymph formation, oedema
protection and formation, lymphatic oedema.

·To draw a model
of the paracapillary circuit and of the two circulatory systems.

·To explain the
exchange between blood and cells, the control of erythropoiesis, Poiseuille´s
law, total peripheral vascular resistance and organ resistance, vascular
compliance and specific compliance, viscosity-related factors, and the
Fåhræus-Lindquist effect.

·The law of
conservation of matter states that mass or energy can neither be created nor
destroyed (the principle of mass balance). This principle is used to measure
physiological blood volumes and bloodflow.

·Poiseuille’s law is
used both in the circulatory and the respiratory system (see Eq.
8-3).

·Afterload is the force against which the ventricle contracts. A good index of the
maximal afterload tension is the peak intraventricularpressure during systole.

·Anaemia is
defined as a clinical condition with an insufficient oxygen carrying capacity
of the blood. A blood haemoglobin concentration below 130 g per l (8 mM)
implies a measurable reduction of the working capacity for both sexes.

·Arterial elastance or stiffness is (DPt/ DV) or the reciprocal of
arterial compliance.

·Arterial pulse
amplitude or thepulse pressure is the difference
between the systolic and the diastolic arterial pressure at a certain level.

·Arteriovenous oxygen
content difference is the difference between the
oxygen concentration in arterial blood and that of the mixed venous blood (CaO2 – CvO2).

·Bloodflow is the flow of whole blood to an organ per time unit. A practical index is the
relative bloodflow measured per 100 g of tissue. Thus, the bloodflow is
expressed in ml of blood per min per 100-g tissue, which is abbreviated as
flow units (FU).

·Bulk flow is
convective transport of fluid with its content.

·Capillary protein
reflection coefficient (s) is the fraction of plasma protein molecules reflected off the capillary wall
following collisions.

·Cardiac output is
the volume of blood leaving the left ventricle (or the right) each min.

·Central venous
pressure (CVP) is the pressure in the right
atrium and caval veins close to the right atrium.

·Compliance of a vessel is the increase of volume per unit of transmural pressure increase
(DV/DPt).
Transmural pressure refers to the intravascular pressure minus the
extravascular pressure.

·Contractility is a measure of the cardiac performance at a given preload and afterload.

·Driving pressure is the mean arterial pressureminus
the atrial pressure or CVP.

·Ectopic focus is a pacemaker focus located in other regions of the myocardium than the
sinus node. Active ectopic foci cause abnormal contraction patterns in the
related regions of the heart.

·Embolism refers to the process through which a thrombus is dislodged from its
attachment and travels with the blood until it is lodged in a blood vessel too
small to allow its passage.

·Erythrocyte
sedimentation rate (ESR) is the rate of fall of
erythrocytes in a column ofanticoagulated blood. ESR is increased, when the plasma is
rich in large sticky protein molecules (fibrinogen, immunoglobulins etc) which
agglutinate red cells, so they fall rapidly. Severe anaemia, immune reactions,
infections, ischaemia, malignancy and trauma increases ESR.

·Fibrinogen is a dissolved plasma protein that can be transferred to a blood cell trapping
fibrin network by the proteolytic enzyme, thrombin.

·Filtration: Transport
across a barrier by means of a hydrostatic pressure gradient.

·Haemolysis refers to disruption of the red cell membrane with liberation of the cellular
content to the plasma of whole blood.

·Haemostasis refers to the arrest of bleeding.

·Hypocoagulability refers to a condition with a prolonged coagulation time.

·Pinocytosis is a process by which fluid and large molecules can pass the capillary wall in
vesicles formed by the cell membrane.

·Preload is
the end-diastolic filling pressure of the ventricle just before contraction.

·Plasma viscosity is measured instead of erythrocyte sedimentation rate (ESR), because it is
dependent of the same large protein molecules as ESR, but independent of
haemoglobin concentration and obtainable within 15 min.

·Pressure is force per area unit. The international unit is Newton per m2 or Pascal (Pa).

·Serum refers to plasma that has undergone coagulation and thus is devoid of
fibrinogen and many other coagulation factors.

·Serum ferritin
concentration (Chapter
22) reflects the mass of stored
iron in the body (normal range 12-140 nM). Most of the ferritin is stored
in the tissues and not in the blood serum.

·Serum iron
concentration (Chapter 22) is Fe2+ bound
to transferrin. The normal range is 7-36 mM
with a mean value around 22 for both sexes. Iron deficiency leads to anaemia
of the microcytic, hypochromic type (small, pale red cells).

·Small-diameter
phenomenon (Fåhræus-Lindquist): The
viscosity of blood decreases in tubes with a diameter less than 0.5 mm,
because the packed cell volume here is relatively low.

·Solvent drag refers
to transport of solvent, which can also draw solutes across a barrier.

·Stroke volume is the volume of blood ejected from a heart ventricle with each beat.

·Thrombosis refers to the formation of multiple thrombi or clots within the vascular
system.

·Total peripheral
vascular resistance (TPVR) is theresistance of the systemic circulation. TPVRcan be calculated as
the driving pressure, divided by bloodflow (Q°s in
ml per s): TPVR = DP/Q°s.During
exercise TPVR is reduced to approximately 30% of the level at rest.

·Transferrin (Chapter 22) is a plasma protein vehicle with 2 binding sites for Fe2+ (normally
35% of the plasma globulin is saturated with iron). Transferrin
saturation is the serum iron concentration divided by the total iron
binding capacity. See iron deficiency.

·Viscosity of blood is the inner friction, which is due to interaction between molecules
and particles in the blood. The viscosity(h)
one Pascal sec (1 Pa s) is the tangential force, working on 1 m2 of
surface area, when dv/dx is 1 (s-1).

The
cardiovascular system consists of two pumps arranged in series (Fig. 8-1). They are the right ventricle that pumps blood into the pulmonary
circulation, and the left ventricle, which pumps blood into the systemic
circulation. Each of these pumps delivers blood through an efferent tube
system (the arteries) and each pump receives blood through an afferent tube
system (the veins). In the pulmonary system, blood is pumped from the right
ventricle through the lung capillaries and is temporary collected in the left
atrium (Fig. 8-1). The coronary arteries are the first arterial branches that
arise from aorta just above the aortic valve. Aorta and the elastic arteries
are conductancevessels;
the muscular arteries are distribution
vessels; the arterioles are resistance
vessels; the capillaries are exchange
vessels; venules and veins are capacitance
vessels. The arterio-venous anastomoses in fingers and toes are shunt vessels.

Fig. 8-1: Design of human circulation with the right heart before and
the left heart after the lungs.

The
principal function of the bloodflow in the cardiovascular system is to provide
oxygen(O2) and
nutrients to the tissues of the body and to remove carbon dioxide (CO2)
and waste products. The flow of blood through the cardiovascular system
follows physical law’s known from fluid mechanics (see principles).

Strictly
speaking, Poiseuille’s law (Eq.
8-3) has validity in a circulatory system, only when the fluid flow is laminar
and non-pulsating in horizontally situated cylindrical vessels of constant
dimensions. The resistance for laminar flow of a Newtonian fluid is only
dependent on the dimensions of the vessel and the viscosity of the fluid.
Resistance varies inversely as the fourth power of the radius of the vessel.

For
resistances in parallel, the total
resistance is less than that of any individual resistance (Fig.8-1 and Eq. 8-4). Although the total cross sectional area of all
arterioles is much larger than that of all arteries, their resistance to
bloodflow is much greater than that of the arteries. The number of daughter
vessels is not high enough to balance the decrease in vessel diameter. The
resistance is highest in the capillaries and it diminishes as the vessels
increase in radius.

For
resistances in series, the total
resistance equals the sum of the individual resistances (Eq.
8-5).

In
contrast to Poiseuille’s conditions, the bloodflow in the human circulation
is pulsating and sometimes turbulent, and its blood vessels are not
horizontally located, cylindrical or inflexible. Neither is the blood
viscosity constant nor independent of vessel diameter and flow.

At rest
the mean red cell velocity in the capillaries is observed to be approximately
1 mm in one s; this provides ample time for gas exchange. Since the
circulating blood moves continuously, the cardiac output must pass a cross
section of all open capillaries. At rest a cardiac output of 5000 ml per min
is a reasonable estimate; when changed into volume rate per s, the cardiac
output is equal to 10-4 m3 s-1. Hence, it is
possible to calculate the large cross sectional area of all open capillaries
in a resting person according to Eq. 8-1 (see Fig.
8-1). The total blood
volume is approximately 5 l in a healthy adult.

The right
atrium receives venous blood from the caval veins, and the left atrium
receives oxygenated blood from the pulmonary veins. The two atria function as
thin walled reservoirs and conduit organs for the blood(Fig. 8-2). On average, atrial systole contributes only about 15 % of
the total ventricular filling, but in cardiac insufficiency the atrial
contribution may increase importantly. The left and right ventricles provide
most of the energy needed to transport the blood through the circulation. The
left ventricle accelerates the blood into the systemic or peripheral
high-pressure system, and its walls are thick in contrast to the thin, weak
right ventricle, which pump blood into the low-pressure pulmonary system.

The left
ventricle consists of cardiac muscle fibres originating from the fibrous
rings at the base of the heart and the fibres are twitching towards the apex.
The orifice between the left atrium and the left ventricle carries two valve
cusps, and this valve is called the bicuspid or mitral valve. Three cusps form the tricuspid valve closing the orifice between the right atrium and ventricle during
systole. Strong filaments (chordae tendineae) arise from the papillary muscles
of the ventricles. These chordae are attached to the free edges of the
atrioventricular valves and normally prevent the valves from bulging into the
atria during ventricular systole. The two atrio-ventricular
valve systems prevent the leakage of blood backward from the ventricles
into the atria (Fig. 8-2). Two other valve systems are interposed between the
left ventricle and the aorta (the aortic valves) and between the pulmonary
artery and the right ventricle (the pulmonary valves).

The conduction system

The
normal heart is characterised by an electrical insulation between the atria
and the ventricles mainly due to the fibrous ring (annulus
fibrosus). However, the heart possesses a specialised electrical system,
the cardiac conduction system that
leads the electrical signal from the atria to the ventricles. The conducting
system consists of modified myocardial cells. An optimal timing of atrial and
ventricular pumping allows the emptying of the atria to be completed before
the ventricular contraction. This allows the heart to pump the required
cardiac output.

The
heart normally has a self-firing unit, located in the right atrium, called the sinoatrial node or sinus node (Fig.
8-2). The sinus node contains round
cells (pacemaker cells), elongated
intermediary cells and ordinary atrial cells. The electrical signal that
automatically originates from the sinus node has the highest frequency, and
the sinus node is thus the natural
pacemaker of the heart. Even a cardiac transplant patient (the heart is
totally denervated) adapts to the altered needs for cardiac function and of
course initiates new heart beats as long as the transplant is functioning.

The
electric signal from the sinus node activates the atrial walls to contraction,
and then reaches the main conduction system at the level of the atrioventricular node (AV node). The AV node consists of the same
cell types as the sinus node. The impulse is delayed in the AV node, and this
delay is allows the atrial systole to squeeze extra blood into the ventricles
just before the ventricular systole occurs (see above).

Fig. 8-2: The cardiac conduction system (left) is the
only electrical connection between the atria and the ventricles of the normal
heart. The anatomy of the four heart chambers is shown to the right.

From
the bundle of His, the signal is
transmitted down a rapid conduction pathway, composed of the right and left bundle
branches, to stimulate the right and the left ventricle and cause them to
contract. The right bundle branch proceeds down the right side of the
ventricular septum, and the large left bundle branch perforates the septum and
divides into an anterior and a posterior division. These bundle branches
divide into a network of conducting Purkinje
fibres just below the endocardial surface. Purkinje fibres are large
diameter cells without T-tubules, and with a long refractive period, so they
can block premature depolarisation waves from the atria. The propagation wave
spreads in the septum from both branches with the thick left bundle branch
being dominant. The spread along the Purkinje fibres is rapid, whereas the
spread from the endocardium to the epicardium is slow (Fig. 8-2).

Ectopic foci become
pacemakers, when the normal dominant pacemakers fail by blockade or
depression: In the AV node, the atria, and the Purkinje fibres or in ischaemic
ventricular fibres.

The
total blood volume (5 l) is distributed with 60-75% in veins and venules, 20%
in arteries and arterioles, and only 5% in capillaries at rest. Of the total
blood volume only 12% are found in the pulmonary low-pressure system.

The
distribution of the cardiac output to the main organ systems of the body in a
healthy person at rest and during maximal exercise is given in Table
8-1.

Table
8-1: Distribution of flow in % of
the cardiac output, arteriovenous oxygen content difference, oxygen
uptake and absolute bloodflow at rest. The same variables are given for
maximal exercise (in brackets).

Organ system

Distribution

A-v difference

O2 uptake

Bloodflow

Flow%

ml STPD* l-1

ml STPD*min-1

ml*min-1

Splanchnic

27
(2)

40
(80)

60
(40)

1500
(500)

Kidneys
(300 g)

22
(2)

12-14
(28)

16
(17)

1200
(600)

CNS

14
(1)

60
(120)

45
(36)

750
(300)

Myocardium
(250 g)

4.5
(6.7)

140
(190)

35
(380)

250
(2000)

Muscle
(35 kg)

19
(88)

50
(160)

53
(4200)

1050
(26 250)

Other
organs

14
(1-2)

50
(100)

38
(35)

750
(350)

Total
body

100
(100)

50
(150)

250
(4500)

5500
(30 000)

A
top athlete can show a 6-fold increase in cardiac output from 5 to 30 l of
blood each min, when going from rest to maximal dynamic exercise. The heart
rate increases from 60 to 180-200 beats per min. The muscle bloodflow can rise
from 3 to 75 ml per min per 100 g of muscle tissue (FU) or factor 25 in a
total muscle mass of 35 kg. The muscular arterio-venous-O2 content
difference can rise from the resting level (200 - 150) = 50 ml STPD per l of
blood to (200 - 40) = 160 ml STPD per l.

At
rest the athlete typically has an oxygen uptake of 250 ml STPD per min. The
total muscle bloodflow at rest is (35 000/100) ×3
= 1050 ml of blood per min. The total muscular oxygen uptake at rest is (1050*
50/1000) = 53 ml per min (Table 8-1).

Accordingly,
the total muscular oxygen uptake rises by a factor of (4200/53) almost 80 from
rest to exercise.

At
the start of exercise, signals from the brain and from the working muscles
bombard the cardiopulmonary control centres in the brainstem (see Chapter
18).
Both cardiac output and ventilation increase, the a-adrenergic
tone of the muscular arterioles falls abruptly, whereas the vascular
resistance increases in inactive tissues. The systolic blood pressure
increases, whereas the MAP only rises minimally during dynamic exercise. The
total peripheral vascular resistance (TPVR) falls during exercise towards 30%
of the level at rest, because of the massive vasodilatation in the muscular
arterioles of almost 35 kg muscle mass (Eq. 8-3). This is why the major
portion of the cardiac output passes through the skeletal muscles (Fig. 18-1)
and why the diastolic pressure often decreases during exercise. At moderate
exercise the skin bloodflow and heat dissipation is increased (Chapter
21).

The
coronary bloodflow increases from rest to exercise (Fig. 10-7 A to B).

Stem cells and red cell precursors contain ribosomal RNA along with cell organels. The cells lose organels during
maturition. Pronormoblasts, normoblasts and reticulocytes at each stage
contain less RNA and increasing amounts of haemoglobin. Reticulocytes can
still synthesise haemoglobin, have lost the nucleus, and remain in the bone
marrow a few days before they enter the peripheral blood. Here, they lose
their RNA after a couple of days and become mature red cells. The
reticulocyte count is normally less than 2.5% of the red cell count, but
following haemorrhage or haemolysis the reticulocyte-% increases reflecting
increased erythropoiesis. When the bone marrow fails to respond to anaemia,
the reticulocyte count may fall below 0.5%.

The
normal haematological ranges are given in Table 8-2, together with other values
of interest.

When
normal kidneys are perfused with hypoxaemic blood, the peritubular
interstitial cells release large amounts of the glycoprotein hormone, erythropoietin, with a strong effect on the haemopoietic stem cells
in the red bone marrow. The stem cells are stimulated to produce
proerythroblasts, which speed up the production of new red cells after a few
days. The increased erythrogenesis improves tissue oxygenation, which decreases erythropoietin production and the
balance is re-established.

Chronic
renal failure leads to erythropoietin deficiency, and thus to anaemia, which
is of the normochromic, normocytic type.

Haemoglobin
is synthesised in the mitochondria of the maturing red cells. Vitamin B6 is a co-enzyme for the formation of d-amino-laevulinic
acid (ALA) by ALA-synthetase. The reaction is stimulated by erythropoietin.
One haemoglobin molecule binds 4 oxygen molecules at most. Haemoglobin
consists of globin(2 a and 2 b polypeptide chains)and 4 prostetic haem-groups (Fig.
8-3). Haemoglobin
A (for Adult) has a molecular weight of 64 460 g per mol (Dalton). Haemoglobin
A comprises almost all haemoglobin in adults, supplied with only a minimum of
haemoglobin A2.

The
polypeptide chains are not covalently linked but are held together by
hydrophobic forces. Each haem group is connected to one polypeptide chain,
which contain a ring of 4 imidazol-groups. In the centre of the porphyrin ring
the one iron atom is coordinated by 6 ligands, four of which bind the metal to
the porphyrin chain, one to histidin on either the a-
or the b-chains.
The last is an open binding, which is able to bind either O2 or
carbon monoxide (CO).

In the
lung capillaries haemoglobin is saturated with oxygen at high tensions, where
the affinity of (oxy)haemoglobin for more oxygen is high (Fig.
8-3). The
affinity between oxygen and haemoglobin is defined and described in Chapter
15, where P50 is introduced as an affinity index. A low P50 equals a high standard affinity and vice versa. The successive change in
affinity during binding of the 4 oxygen molecules to each haemoglobin is
caused by molecular interactions among the 4 haem groups. This explains the
sigmoid shape of the oxygen dissociation curve (Fig.
15-3). Oxygen is released
at the low tensions of the tissues, where the affinity of (deoxy)haemoglobin
for oxygen is low. The oxygen tension in the tissue mitochondria may reach
extremely low values (zero to 1 mmHg or 0.133 kPa).

Red
cells do not contain mitochondria, so they survive on anaerobic metabolism
(glycolysis) and the anaerobic intermediate, 2,3-diphosphoglycerate (2,3-DPG), is produced by the help of a red cell enzyme. As the 4 haem units
successively unload oxygen, the b-chains of deoxyhaemoglobin are pulled apart,
and 2,3-DPG binds strongly to the 2 b-chains of deoxyhaemoglobin (Fig.
8-3). This
electrostatic binding substantially reduces the affinity between oxygen and
haemoglobin. – Individuals with high arterial pH (chronic alkalosis) or with
low arterial oxygen tension (hypotonic hypoxaemia) increase their
concentration of 2,3-DPG in their red cells. Storage of blood reduces the
2,3-DPG concentration with time.

When
haem is bound to O2 or CO, it has a cherry-red colour, and haem is
dark red when it is in the deoxygenated form. The breakdown of haemoglobin
liberates CO and produces bilirubin that is yellow in colour. Bilirubin is
normally excreted with the bile. Failure of bile excretion leads to
accumulation of bilirubin in the body. Jaundice (icterus) is a yellow pigmentation of the skin, plasma, cell membranes and
secretions with accumulated bilirubin and other bile-pigments. Bilirubin and
other pigments are also found in the blue-yellow skin-spots following lesions
with subcutaneous bleeding.

Notice
that when blood is saturated under the normal, ambient O2 partial
pressure (20 kPa = 150 mmHg), the oxygen
capacity of haemoglobin is 1.34 and not 1.39 ml STPD g-1 (Fig.
8-3). The latter holds only for extremely high partial pressures (above 45
kPa), when breathing pure oxygen or oxygen enriched air, where the oxygen
capacity is equal to the theoretical.

The
rate of fall of red cells is called the erythrocyte
sedimentation rate (ERS). The ERS is measured in a glass column of whole
blood with anticoagulant. ERS is measured in mm as the cell free yellow zone
above the red cells following 60 min of sedimentation. ERS is an estimate of
the acute phase response. The acute phase response produces high levels of
large sticky proteins (C-reactive
protein, immunoglobulins, fibrinogen) that form rapidly falling piles of red
cells. ERS is abnormally increased (above 20 mm) in infections, immunology
reactions, ischaemia, malignancy or traumas. Normally, the level is only a few
mm per first hour, 15-20 with a common cold, and 50-100 during pregnancy.

Viscosityis the inner
friction in the fluid, which is due to the interaction between molecules
and particles in the blood passing a cylindrical vessel. Telescope cylinders
(laminae) of blood sliding against each other (Fig. 8-4) can illustrate this
inner friction. The outermost blood cylinder rests against the vessel wall
(velocity is zero), and the central cylinder moves (laminar flow) with the
greatest velocity (v). The velocity profile is parabolic. The velocity gradient, with the distance x from the centre of the blood
vessel towards the outermost blood cylinder, is called the shear rate (dv/dx). The
tangential force (F) between these
blood cylinders depends upon the area (A)
sliding against each other, and the relation to viscosity (h)
is given by the equation in the legend to Fig 8-4.

F/A
= h×dv/dx. The viscosity (h)
one Pascal sec (1 Pa s) is the tangential force, working on 1 m2 of
surface area, when dv/dx is 1 (s-1).

This
simplified description is valid for water, gas, and other homogenous fluids
that are Newtonian fluids. Newtonian
fluids are defined as fluids with a
viscosity that is independent of the shear rate. Newtonian fluids move
streamline or with so-called ideal laminar flow.

The
viscosity of non-Newtonian fluids decreases with increasing shear rate,
according to the equation above. Blood is namely not homogenous with a
viscosity that is independent of shear rate. On the contrary, at low shear
rates (low bloodflow), the viscosity of blood can be ten-fold higher than
normal. The typical normal viscosity of body warm blood is 5 centiPoise equal
to 5 milli-Pascal seconds or 5 (mPa*s).

Blood
viscosity depends upon the concentration of red cells (the haematocrit).

Fig 8-5: Haematocrit (PCV) and relative viscosity
varies along the green line. A normal PCV of 45% is shown with the normal
absolute viscosity of body-warm blood.

A patient with anaemia and a PCV of 30% has a low blood viscosity and a poor
oxygen transport capacity (Fig. 8-5). On the contrary, a patient with
polycythaemia and a PCV of 60% has a high oxygen transport capacity, but the
blood viscosity is dangerously high and he may develop thrombosis and emboli
(Fig. 8-5).

With
increasing bloodflow (and shear rate), an increasing fraction of red cells is
being pulled into the axial stream of small vessels, so that friction is being
minimised. At high shear rates in large vessels, blood therefore mainly
behaves like a Newtonian fluid, with a low and almost constant viscosity, as
well as a linear relation between bloodflow and the driving pressure.

The
viscosity of blood apparently decreases in tubes with a diameter less than 0.5
mm (the small-diameter effect - or the Fåhraeus-Lindqvist phenomenon - see
Fig. 8-6).

This is
because the packed cell volume (PCV) is low in small vessels, since red cells
have a tendency to accumulate and pass as a single plug in the fast axial
stream, where there is a negligible friction. The slower layers along the
vessel wall are passed mainly by plasma. This falling viscosity in the small
resistance vessels and in the precapillaries and capillaries reduces the work
of the heart. This is why the bloodflow frequently rises linearly with the driving pressure and thus actually follows Poiseuille´s
law, as if blood was a Newtonian fluid.

Bloodflow
tends to become turbulent in irregular vessels, where the flow velocity is
high and the viscosity is low. Turbulence means irregular movements of the
fluid elements - an energy demanding transport process.

Plasma viscosity is
sometimes measured instead of erythrocyte sedimentation rate (ESR), because it
is dependent of the same large sticky protein molecules as ESR, but is
independent of the haemoglobin concentration and obtainable within 15-20 min.

Whole
blood consists of a fluid (plasma) in which blood cells and platelets are
suspended. Blood cells consist of red cells (erythrocytes) and white cells
(leukocytes). A small amount of anticoagulant to a blood sample blocks the
coagulation process, and whole blood sediments into three layers: Below the
heavy red cells, then a thin grey-white layer of white cells, and above a
yellow fluid (plasma) with an invisible content of most of the platelets. A
blood sample without anticoagulants normally sediments with coagulation
(fibrin formation) within 5 min. A firm red mass is formed, and after some
time it retracts and forms a red cone (a fibrin clot of blood cells and
fibrin) surrounded by yellow serum.

Healthy
humans possess both a fast extrinsic and a slow intrinsic clotting system. The
coagulation process involves at least 3 systems all contributing to the
haemostasis. Firstly, a vasoconstriction occurs following release of serotonin from damaged endothel cells.
Secondly, the fast extrinsic system goes
into action, and thirdly, the slow
intrinsic system contribute. Finally, the 2 coagulation systems operate
together and converge for common reactive steps in order to produce thrombin (Fig.
8-7).

Disruption
of the endothelial barrier by injury initiates a cascade of catalytic events
through either or both clotting systems. At each reaction in the chain of
events, a proenzyme coagulation factor is activated to its enzymatic form,
which can activate the next reaction in the chain. The letter a stands for the active form. The enzymes are all endopeptidases (proteases),
and their catalytic sites include a serine moiety.By these many steps in the cascade, the process escalates until large
amounts of thrombi are released. - Factor IV (Ca2+), factor V
(proaccelerin), kininogen, kallikrein, and factor VIII are coagulation
co-factors without enzymatic activity.

Thrombinis a protease that is
responsible for the formation of fibrin monomers, and thus for formation of a
fibrin clot. Its parent molecule is prothrombin (factor II), which is present
in normal plasma. Thrombin formation from prothrombin goes through certain
cleavage stages, the first of which is by activated factor Xa (Stuart). These
reactions are augmented by factor IV (Ca2+), factor V
(proaccelerin), and phospholipid (see green oval in Fig.
8-7). Thrombin
initiates blood platelet aggregation, and disintegrates the plasma membrane of
the platelets so phospholipid is provided. The coagulation factors are
synthesised mainly in the liver. - An exception is the large Von Willebrands
factor (vWf) complex, which is synthesised in the vascular endothelial cells
and in megakaryocytes.

The fast
extrinsic thrombin formation is initiated by the contact of blood with
injured cells (Fig. 8-7). The damaged cells liberate a clot-promoting agent,
factor III or tissue thromboplastin. Factor III interacts with a plasma protein,
factor VII, to start a cascade of reactions by prothrombin activators leading
to formation of thrombin within seconds (Fig. 8-7).

Clotting
of blood implies conversion of a soluble plasma protein, factor I (or
fibrinogen), into an insoluble network of fibrin. First, fibrinogen undergoes
limited proteolysis by thrombin. The formed fibrin monomers polymerise into
insoluble strands of fibrin polymers (Fig. 8-7). Finally the monomers of the
fibrin strands are cross-linked by the enzyme activated (a) fibrin-stabilising
factor (XIIIa).

Fig. 8-7: Blood coagulation and fibrinolysis. The
roman numbers were originally introduced as a short-cut.

When
venous blood is drawn in silicone coated tubes and centrifuged for the
separation of cells and plasma, the isolated plasma clots readily, due to the
negative surface charge of glass.

In the
absence of thromboplastin, thrombin is formed via the intrinsic clotting system.Negatively
charged surfaces on damaged cells generate thrombin, trigger inflammatory and
immune responses and even activate fibrinolysis.

The
first step is that negatively charged surfaces (artificial or injured
endothelial barrier) activate factor XII (Hageman) to XIIa, which can activate
factor XI in the presence of kininogen. The factor XIa activates the
vitamin-K-dependent protein, Christmas factor (IX). Christmas factor is
synthesised under the control of a gene on the X-chromosome. Activated
Christmas factor (IXa) converts factor X to its activated state (Stuart factor
Xa). Stuart factor is a plasma proenzyme - also vitamin-K-dependent. The Xa is
the enzyme immediately responsible for the release of thrombin, and the final
steps of the two clotting systems are identical (Fig. 8-7). Hepatocytes
produce factors X, IX, VII, and II only when vitamin K is present.
Insufficient synthesis of these coagulation factors can lead to serious
bleeding.

When
the endothelial surface of the vascular system is disrupted, platelets
normally adhere instantly to exposed structures (collagen and other fibres).
Adherent platelets discharge ADP and other substances. Adherent platelets
become spherical and send out spicules that look like the legs of a spider.
The platelet plug grows and forms a firm haemostatic plug that stops the
bleeding. Platelets provide substances that enhance thrombin production, such
as phospholipid, the important cofactor in the clotting process.

Blood
has the ability to dissolve clots. Fibrinolysis is the dissolution of fibrin.
The hepatic plasma glycoprotein proenzyme, plasminogen, is activated to the
serine protease, plasmin (Fig. 8-6). Streptokinase, staphylokinase and
urokinase convert plasminogen to plasmin. The tissue plasminogen activators
are serine proteases. Stress, muscular activity and emotional crises enhance
fibrinolysis. Plasmin digests fibrin, fibrinogen and other clotting factors.
If plasmin is formed in blood plasma devoid of clots, it is irreversibly
inhibited by a2-antiplasmin
(Fig 8-7).

The
coagulation process is normally modulated to the needs of the person by
inhibitors within the blood. Antithrombin III is the main inhibitor of
thrombin and factor Xa, and its effect is potentiated by heparin. Heparin is a
negatively charged mucopolysaccharide from mast cells. Heparin binds to
antithrombin III forming a complex that rapidly binds serine proteases such as
thrombin, thus functioning as a potent anticoagulant. Heparin alone does not
inhibit the coagulation process significantly. Heparin
is used during artificial perfusion such as dialysis and open heart
surgery. Exogenous plasminogen activators are used to dissolve clots in the
coronary arteries.

Fibrinolysis
is inhibited mainly by a2-antiplasmin,
because plasmin combines with antiplasmin in an irreversible link (Fig 8-7).

Vitamin
C or ascorbic acid cannot be synthesised in humans, but the vitamin is present
in all fresh fruit and vegetables. Hydroxylation of proline to hydroxyproline
is necessary for the formation of collagen and thus of the normal tissue
including blood vessels. Lack of vitamin C (scurvy) leads to defective blood
vessel walls with spontaneous haemorrhage and blue spots.

Distensibility or
compliance is the increase of volume per unit of transmural pressure increase
(DV/DPt).
The specific compliance is the relative increase in volume per unit of
pressure increase. The elastance or stiffness is the reciprocal value of the
compliance. The compliance of the venous system can be 30 times as large as
that of the arterial system.

The
venous system can be expanded to contain more than 75% of the total blood
volume. The veins function as capacitance vessels, and become very distended
when blood is given in transfusions, in heart insufficiency, or during a heart
attack. Severe exercise and loss of blood cause an increase in venous tone,
which for a period actually can increase the circulating blood volume. During
hard work the muscular venous pump provides up to 1/3 of the energy required
for blood circulation (the peripheral venous heart). The venous system also
plays an important role by its graded venous return to the heart.

Fig. 8-8: Recording of the arterial blood pressure at rest.Dashed, horizontal lines depict MAP. The pulse pressure of the
abdominal aorta is calculated from the arterial compliance of a young person
at rest.

The
recording shows a systolic peak pressure, a dicrotic notch as the aortic
valves close, and a falling diastolic pressure. The yellow area under the
dashed green line equals the yellow area above the line (Fig. 8-8).

The
mean arterial pressure, MAP, is usually being defined as the diastolic
pressure plus 1/3 of the pulse pressure (Fig. 8-8). The mean arterial pressure
(MAP) is about 12 kPa (= 90 mmHg) in the arteries. Notice the fall in MAPfrom the
abdominal aorta to the femoral artery, whereas the systolic pressure increases. The arterial mean pressure falls to a mean value around 2.4 kPa (18 mmHg)
in the capillaries.

The arterial
pulse pressure is the difference between the systolic and the diastolic
arterial pressure. At a heart rate of 75 beats/min at rest, the cardiac cycle
length is 0.8 s with 0.3 s systole and 0.5 s diastole. A stroke volume of 70
ml is deposited in the aorta and the larger elastic arteries during systole.
During the systolic period 26 ml of blood(70×3/8)
is streaming through the resistance vessels, leaving the arterial system, so
the systolic volume expansion is 44
ml of blood. A young healthy subject has an arterial distensibility or
compliance of 1 ml of blood per mmHg, which creates a pressure rise during
systole (pulse amplitude) of (70-26) = 44 mmHg (Fig. 8-8). With a diastolic
pressure of 70 mmHg, this implies a systolic pressure of 114 mmHg,
conventionally written 114/70 mmHg or 15.2/9.3 kPa.

Aging
and arteriosclerosis increase the stiffness (reduce the distensibility) of the
elastic arteries, causing the arterial compliance to fall from 1 (one) to 0.5
ml of blood per mmHg. In this case, a systolic volume expansion of 44 ml of
blood increases the pulse pressure amplitude to 88 mmHg (44/0.5=88), and the
blood pressure to perhaps 180/92 mmHg. This is a likely process in an
otherwise healthy person of advanced age. Typically, the average diastolic
pressure will rise with age.

For a thin-walled organwith
two main radii, Laplace predicted that thetransmural pressure at equilibrium (DPt),
was identical with the fibre tension in the wall (T)divided by the two main radii: DP
= T /(r1 + r2). This model
has often been used (withmodifications for wall thickness, w)
for the relaxed ventricle (Fig. 8-9A).

For
a thin-walled spherical organ (r1 = r2 = r), another Laplace equation can be developed from the equation
above (Fig. 8-9B). This model is often used for both alveoli and the spherical
ventricle. When the left ventricle becomes more and more spherical by
diastolic filling, the T will rise
with the transmural pressure. The radius increases with the end-diastolic
volume.The more the
end-diastolic pressure and the fibre tension rises, the higher is the energy
demand and the more O2 is consumed per heart beat during
contraction of the dilatated ventricle.

For
an infinitely long thin-walled cylinder,like a true capillary or a preferential channel (see below), the r2 approaches infinity and has no influence on the
transmural pressure. Hence, the Laplace equation can be approximated by eq.C
in Fig. 8-9C. This model is used for a thin vessel wall, since T/r2 approaches zero. Surprisingly enough, the thin endothelial barrier (0.3 mm)
of a capillary easily carries a pressure of 4.3 kPa (32 mmHg) or more. This is
because the capillary radius is so small. According to eq. C in Fig. 8-9C, a
small radius (5-10 mm)
must imply a small wall tension (T).

In
hypertension, the arterial walls hypertrophy, so the wall tension is minimised
and hence the risk of vessel rupture (use Eq. 8-9C with correction for wall
thickness: T = DP* r/w).

The
microcirculation is responsible for the transport of nutrients and oxygen to
the tissues, and for removal of cellular waste products and CO2.
The arterioles control the flow of blood to each tissue unit, and the
metabolic conditions of the tissue cells determine the diameters of the
vessels. Hereby, the tissue unit often controls its own blood flow by local
mechanisms.

A microcirculatory
unit is a collection of vessels that originate from an arteriole, which is
characterised by well-developed smooth musculature in its wall (Fig.8-10).
Arterioles of the face, fingers and toes often branches into an arteriovenous anastomose, which functions as a shunt vessel, but
which also can be closed completely. In certain tissues the arteriole branches
into metarterioles (with so-called precapillary
sphincters of smooth muscle fibres without nervous supply), which continue
into large capillaries termed preferential
channels (or thoroughfare channels). These channels shunt the blood to the
veins. The small true capillaries have only a thin endothelial cell layer
making the wall ideal for exchange

The
diameter of true capillaries is only
5-10 mm,
barely enough for erythrocytes to squeeze through. The average length of
capillaries is 1 mm, and the linear red cell velocity at rest varies around 1
mm each s. The capillary density is high in cardiac and striated muscle tissue
and low in subcutis and in cartilage. Endothelial cells contain actin and
myosin. It is uncertain whether capillaries may be able to alter their shape
according to the needs of the tissues.

Important exchange vessels are thin-walled
vessels with a large surface area. Exchange vessels comprise true capillaries,
parts of preferential channels, and venules (Fig. 8-10). The number of pores
is high in the venous ends of capillaries and in venules. Exchange vessels are
any blood vessels, which allow transport of substances through its wall in
both directions. The velocity of the bloodflow in capillaries varies,
sometimes with rhythmic pulsation, at other times random.

At rest
the intracapillary pressure varies from arteriole to venule between 3.3 and
1.6 kPa (25 and 12 mmHg), during arteriolar vasoconstriction between 1.6 and 1
kPa (12 and 8 mmHg), and during vasodilatation between 5.3 and 1.6 kPa (40 and
25 mmHg). Arterial pressure fluctuations have been recorded even in the most
distal parts of the capillaries. In venules and veins, however, the flow is
smooth without fluctuations.

The
capillary wall consists of a layer of endothelial cells (0.1 - 1 mm
of thickness) resting on a basement membrane. At least three types of
capillaries are present in humans:

1.
Continuous capillaries are the most abundant.
The distance between endothelial cells is 5-30 nm (Fig.
8-11). Tight junctions
with narrow clefts are difficult to pass for the dissolved molecules and ions.
In the continuous capillaries, the water filled pore surface area comprises
only 10-4 of the total surface.

The
continuous capillaries in the brain are low permeable to ions and most
hydrophilic molecules, because their tight junctions are really tight (theblood-brain barrier).

2.Fenestrated capillaries contain tight
junctions and pores or fenestrations, which are fluid filled channels with a diameter of
50-100 nm. These are formed by two adjacent cell membranes that have fused
during removal of the lipid bilayers, so only a diaphragm of protein lattice
is left allowing bulk flow without colloids (Fig. 8-11). Fenestrations are
round windows found in the capillaries of organs that transport lots of water
(the bowels, glomerular capillaries of the kidneys, pancreas and salivary
glands). In each fenestration a bush-like filaments can be demonstrated by
electron micrography (Rostgaard). The filaments are composed of a protein core
with glycosaminoglycan side chains. The filaments and the protein lattice in
the fenestrae keep plasma proteins back (Fig. 8-11). In the glomerular
capillaries, water filled fenestrations cover 20% of the surface.

3.Sinusoid capillaries have very broad
openings between the endothelial cells (Fig. 8-11). These large fenestrations
have no diaphragm. Sinusoid capillaries are often found in tissues that are
bathed in plasma (liver, spleen and bone marrow).

The circumventricular
organsof the brain contain
lots of fenestrations in the walls. The circumventricular organs are located
close to the control centres of the hypothalamus and the brainstem. Any
penetration of signal molecules in the neighbourhood of these control centres
is of physiological importance. - In other areas with continuous capillaries,
most substances cannot bypass the blood-brain barrier and reach the brain
cells.

Starling
hypothesised that the fluid exchange across the capillary wall was determined
by the hydrostatic (Pc)
and the colloid osmotic pressure (pc) in
the capillary (Fig. 8-12).

Fig.
8-12: Transcapillary fluid exchange (Starling) is shown over a capillary wall.
The pressures are in mmHg. The capillary filtration coefficient is in ml*min-1*kPa-1*(100
g tissue)-1. One mmHg equals 133.3 Pa.

The
flux of substance (J) over the
capillary membrane is determined by (P×DC).
Actually, this is nothing but an extension of Fick’s
law for diffusive transport (Eq.
1-2).

Fluid
moves out of the arterial end of the capillary by filtration, because the net hydrostatic pressure (35-5 = 30 mmHg) is higher than the
colloid osmotic pressure (pc=
26 mmHg), and most of the fluid (9/10) passes again into the blood by reabsorption in the venous end (Fig. 8-12). Here, the colloid osmotic pressure (26
mmHg) supersedes the hydrostatic pressure (15-1 mmHg equals14 or 1.9 kPa).

The net
diffusion of water molecules across the capillary wall is approximately zero.
Instead, the transvascular exchange is caused by a combination of an outward
ultrafiltration and an inward
colloid osmotic force. Ultrafiltration is caused by a hydrostatic pressure
gradient created by the heart. The hydrostatic pressure gradient is a net
outward force, moving water through pores in the capillary wall. Plasma
contains dissolved protein, which cannot pass the small pores in capillary
walls readily. The plasma proteins create a colloid
osmotic pressure of about 3.3-3.7 kPa (25-28 mmHg). This pressure is much
larger than the interstitial colloid osmotic pressure, so that the colloid
osmotic gradient across the capillary wall is a net inward force, which draws
water into the capillaries.

Starling
in Eq. 8-7 described the transvascular water flow as early as in 1896. The
driving forces are the so-called Starling
forces (see Eq. 8-7). The capillary
protein reflection coefficient is symbolized s.s is the fraction of plasma protein molecules reflected off the capillary wall.
The protein reflection coefficient is 0.9-1.0 for many capillaries, expressing
that the colloid osmotic pressure gradient is not reduced over time by
diffusion of proteins over the capillary wall.

The capillary
filtration coefficient (Capf)corresponds to the permeability of
the capillary wall. In the legs Capf is around 0.075 ml of fluid
per min per kPa in 100 g of tissue (at body temperature). The combined
pressures in the Starling equation ([(Pc - Pt) - s(pc - pt)])
determine, if there is a net pressure for
water movement across the capillary wall (Eq. 8-7).

In
conclusion, water moves out of the arterial end of the capillary by filtration, and near the venule end, water moves into the blood by reabsorption. This transport along the capillary is called Starling´s paracapillary circulation. Thus there is normally a net
filtration of water and some proteins into the interstitial space. This water
and protein, returns to the blood via the lymphatic system (1/10 of the total
filtration in Fig. 8-12). The lymph volume amounts to approximately 3-5 l
daily, and is mainly produced in the liver and intestine. Starling presumed
– erroneously - that proteins were unable to leave the blood in the
capillaries (Fig. 8-13: A).

Fig. 8-13: Two models of transcapillary fluid
exchange. The capillary pressure (Pc) is protected from large changes in MAP,
but is sensitive to changes of venous pressure including the central venous
pressure.

This
assumption is wrong. The capillaries are almost universally permeable to
proteins and macromolecules that resemble proteins.

Another
physiologist Drinker found protein in lymphatic fluid. Drinker developed a
model, which presumed that capillaries to a variable degree were permeable to proteins (Fig. 8-13: B). Within a single capillary, the protein
permeability increases from the arterial towards the venous end.

Let us
assume that the heart is pumping out about 9000 l of blood every day. With a
packed cell volume of 45% there is 55% plasma. This means that 4950 l is
plasma. With a 6% protein concentration there is a total of 297 kg of protein.
If less than 0.1 per cent (1/1440) of this protein is filtered into the
interstitial fluid and lymph, it amounts to 206 g of protein daily. This
amount of protein leaves the blood in the capillaries, and returns almost
completely to the blood through the lymph and not the veins (Fig. 8-13: B).
Hence, Starling’s paracapillary
circulation obviously plays a dominating role in the transport of crystalloids (small molecules of nourishment and waste products) through the capillary
wall.

The capillary
hydrostatic pressure (Pc)
varies from tissue to tissue. It is low in the lungs and intestine (1 kPa) and
particularly high in the renal glomerular capillaries (6-8 kPa). In resting
skeletal muscle capillaries, the pressure is 4.3 kPa (32 mmHg) at the arterial
end and 1.6 kPa (12 mmHg) at the venous end. In general, Pcincreases whenever the mean arterial
pressure (MAP) increases, venule pressure (Pv)
or resistance (Rv)
increases, or when arteriolar resistance (Ra)
decreases, according to the formula: Pc = [(Rv/Ra)
MAP + Pv] developed in Fig. 8-13. Normally, Rv/Ra is approximately 1/10. Thus Pc is protected from large changes in
MAP, but is sensitive to changes in
venous pressure including the central venous pressure (CVP).

In
tissues, where the perfusion pressure is reduced to a value below a so-called critical
closing pressure, the bloodflow ceases due to vessel collapse. This is
explained by the Laplace model (Fig. 8-9C).

Macromolecules
do penetrate the capillary wall and the content of lymph derives from plasma.
Less than 0.1 per cent of all the plasma proteins that are being ejected from
the heart in 24 hours, escapes from the capillaries. The venous end of the
capillaries is permeated by pores of 40 - 60 nm. Here, macromolecules can pass
by filtration in a pressure determined fluid transport. Passage as a whole
plasma portion (bulk flow) through fenestrations is also possible.

Transepithelial
solvent transport can also draw solutes by solvent
drag. Gradient dependent transport concepts such as filtration, bulk flow
and solvent drag are used by different groups of scientists. When large
amounts of lymph is being produced, solvent drag dominates over diffusion. At
low lymph production, half of the protein transport is caused by diffusion.
Fluid pass through the cell by pinocytosis.

Capillary filtration predominates over capillary reabsorption resulting in an overshoot (a net filtration) of interstitial fluid. Most
of the net filtration is reabsorbed into the blood of end-capillaries or
venules (Starling´s paracapillary circulation).

The lymphatic vesselsdrain the remaining
filtered fluid (Fig. 8-12). The lymphatics are composed of endothelium-lined
vessels similar to blood capillaries. Some lymphatics are equipped with
one-way valves, so rhythmic activity in nearby skeletal muscles returns the
lymph to the circulation via the thoracic duct. Lymph vessels originate as blind-ended
sacs close to the blood capillaries. Lymph vessels are permeable to
proteins, macromolecules and even to cells from the interstitial fluid. The
lymphatic drainage is particularly important for transporting chylomicrons absorbed from the intestine, and to return plasma proteins that leaks from
several blood capillary systems. Lung tissue has no lymphatics, because the
lymphatic vessels end at the terminal bronchioli. The lymph from the liver
provides us with 50% of the daily lymph produced.

Lymphatic fluids from liver and kidney have a protein concentration equal to plasma’s (6-8 g per 100 ml), and
lymphatic fluid from the bronchial tree has a similar concentration of
protein.

Lymphatic fluids from skin and muscles contain only 2% protein, and brain lymph contains no protein at all.

Anaemiais defined as a condition with an insufficient
oxygen carrying capacity of the patients blood. For both sexes and all age
groups a blood haemoglobin concentration below 130 g per l (8 mM) implies
reduced working capacity and thus a consequential clinical condition.
Reference levels for age and sex are also available, but they differ from
laboratory to laboratory.

Mean corpuscular volume (MCV)
expresses the mean volume of each red cell. MCV is calculated from the packed
cell volume (PCV) by division with the red cell count. An example with normal
values provides the following: 0.45 (l/l)/5*1012 (red cells/l).
Thus MCV is equal to 90*10-15 l per red cell. One femtolitre (1 fl)
equals 10-15 l. The normal
range is 80-96 fl. The MCV index is used to classify anaemia’s into
microcytic (MCV<80 fl), normocytic (MCV 80-96 fl) and macrocytic forms (MCV
>96 fl), but the classification is not causal.

Mean corpuscular haemoglobin concentration (MCHC) provides the mean concentration in each red cell. MCHC is calculated
from the haemoglobin concentration by division with the packed cell volume
(PCV). An example with normal values provides the following: 150 (g/l)/ 0.45
(l/l). Thus, normal MCHC is 333 g per l
of red cells. Since the concentration of haemoglobin in a normal red cell
is maximal, the maximal value (380 g/l) is the highest occurring. Normochromic
anaemia’s have MCHC values in the range 320-380 mostly within 320-350
g/l. Anaemia with MCHC below 320 g/l is called hypochromic,
and they are often also microcytic such as in iron deficiency anaemia.

Anaemias are classified
into two groups based on their cause. The first group isdeficiency anaemias with
insufficient haemoglobin production due to dietary/ absorptive defects or to
bone marrow hypoplasia from cell destruction by chemicals or radiation (Table
8-3).

A3. Sideroblastic
anaemia (defect synthesis of haem) with ring
sideroblasts, is genetic or acquired. The genetic type is X-linked and
transmitted by the mother. The acquired types are caused by alcohol, drugs,
lead, other disorders or the cause is unknown (primary type). Sideroblastic
anaemia is characterised normal total iron binding capacity, raised serum-iron
and raised serum-ferritin.

A4. Macrocytic
anaemiawith megaloblasts in the bone marrow is due to
folate deficiency or to vitamin B12 deficiency.

Folate deficiency anaemia is
recognised when the folate concentration in red cells low. This deficiency is
due to poor intake, malabsorption, antifolate drugs and excess utilization.
Since the folate stores of the body are low the anaemia develops rapidly (over
months) compared to years for pernicious anaemia.

Folate polyglutamates are synthesized in human cells. These compounds are
biologically active, as coenzymes in amino acid metabolism and in the DNA
synthesis. The synthesis of the biologically active form of folate is
dependent of vitamin B12. Lack of folate
inhibits the purine-pyrimidine-DNA-synthesis, and without new DNA cell
division is seriously reduced. The typical patient appears with glossitis and
a megaloblastic anaemia is found. The amount of folate in red cells is below
160 mg
ml-1. The normal range is 160-640mg
ml-1.

Pernicious anaemiais the most common cause of vitamin B12 (cobalamin) deficiency. Pernicious anaemia is characterised by a low
serum-[vitamin B12](below
160 ng l-1). Megaloblastic anaemia with lack of gastric HCl
confirms the diagnosis.

Pernicious
anaemia occurs in three forms: 1) most patients have an autoimmune disorder, with plasma antibodies against their own
parietal cells; 2) rarely, new-born babies suffer from congenital intrinsic factor deficiency with normal pepsin and acid
secretion; and 3) finally as vitamin B12malabsorption, because of a defect in the intrinsic factor-B12receptors in the terminal ileum.

Vitamin
B12 malabsorption in adults is caused by one of two intrinsic
factor antibodies. One antibody blocks the binding of intrinsic factor to B12,
so the protease-resistant complex is never formed. The other intrinsic factor
antibody blocks the binding of the intrinsic factor- B12 complex to
the intrinsic factor-B12 receptors of the terminal ileum. The
result is vitamin B12 malabsorption.

Parietal
cell antibodies are present in the
plasma of 90% of all patients with pernicious anaemia. The parietal cells of
the gastric glands fail to secrete HCl and intrinsic factor. Intrinsic factor
is a glycoprotein, which combines with vitamin B12 of the food.
This combination normally makes vitamin B12 available for
absorption in the ileum. The site of red cell production is the red bone
marrow, which is normally one of the most proliferative tissues.

The
lack of vitamin B12 in the liver and the red bone marrow inhibits
the methyl-malonyl Co-A mutase and
also spoils the purine-pyrimidine-DNA-synthesis.
The inhibition of these and other processes leads to the neurological and the
haematological disorders in pernicious anaemia.

The neurological features are progressive polyneuropathy with
degeneration of the posterior and lateral column of the spinal cord and
peripheral nerves (eg, optic atrophy, symmetrical paraesthesia, weakness,
dementia and ataxia).

Haematological disorders.
Lack of vitamin B12 in the bone marrow turns the normal
erythroblasts into abnormal megaloblasts. The erythrocyte production is
inhibited, and the cells synthesise much more RNA than normal and much less
DNA. Besides, the formation of leucocytes and platelets suffer causing
leucopenia and thrombocytopenia. Instead of normal erythrocytes, the
megaloblasts deliver megalocytes to the circulation. Megalocytes are fragile and only have an average life of 40 days, as
compared to 120 days for adult erythrocytes.

Cobalamine is the
chemical name of vitamin B12. Pernicious anaemia is treated with
intramuscular injections of hydroxycobalamin storage, followed by 1 mg every 3
months as long as the patient lives.

A5. Macrocytic
anaemia without megaloblasts in the bone
marrowis a physiological anaemia
in pregnancy and in new-born babies. This anaemia is also found in patients
with alcohol abuse, hepatic disorders, hypothyroidism, and aplastic anaemia.
The concentration of vitamin B12 and folate in the plasma is
normal. The relative number of reticulocytes and the MCV is increased. – In
some cases there is fat accumulation in the red cell membrane, but the
pathogenesis of these conditions is not clarified.

A6. Aplastic
anaemia refers to a condition of bone marrow
failure with only few pluripotent stem cells in the bone marrow. This is due
to immune suppression of stem cells by T suppressor cells, or to direct
destruction of the stem cells caused by chemicals, drugs, infection or
radiation. Pancytopenia, absence of reticulocytes and an aplastic bone marrow
is characteristic.

B1. Acute
bleeding(loss of red cells). Normochromic normocytic
anaemia occurs following an acute bleeding with plasma dilution, before the
iron stores are depleted. - Lack of vitamin K can change the development of
even a simple tooth bleeding to a serious condition.

In
most cases of anaemia the fall in transport capacity develops slowly, whereby
there is time for physiological adaptations to minimise symptoms and signs. A
rise in 2,3-DPG improves the release of oxygen to the cells. Unspecific
symptoms such as fatigue, headaches and faintness have varying origin and are
not always recognised as a disease. Dyspnoea, palpitations, cardiac cramps,
and intermittent claudication are also difficult to interpret. The signs of
anaemia are tachycardia, systolic murmur over the heart, and cardiac failure.
Drumstick fingers with spoon-shaped nails are seen in chronic anaemia with
hypoxia such as in chronic iron deficiency. Jaundice suggests the possibility
of haemolytic anaemia.

The
falling red cell count reduces the oxygen delivery but also leads to falling
viscosity of the blood. The reduced viscosity can reduce the total peripheral
vascular resistance (TPVR) to less than half of the resting value, which is an
appropriate event, since it easens the cardiac work and improves the
bloodflow. A slight fall in systemic arterial pressure reduces the stimulus of
the arterial baroreceptors, and causes a rise in heart rate and cardiac
output. The low oxygen capacity of haemoglobin is compensated by an increased
coronary bloodflow at rest. The myocardial anoxia results in cardiac failure
(Fig. 10-10) with oedema, large liver, and stasis of the neck veins. Severe
anaemia increases respiration, metabolic rate, and temperature due to the
large cardiopulmonary work.

Oedema is an abnormal
clinical state characterised by accumulation of interstitial or tissue fluid.
Cutaneous oedemas can be diagnosed by the simple test: pitting on pressure.
Theoretically, oedemas are caused by three different mechanisms:

1.A hydrostatic pressure gradient, which is too great
(so-called high pressure oedema or cardiac
oedema at heart failure with increased venous and central venous
pressure),

3.Leakage in the capillary endothelium (so-called permeability
oedema with too much protein in the oedema fluid). Burns cause increased
capillary permeability for proteins, by infections or by allergy.

Cardiac oedema develops in the dependent parts of the human body, where the hydrostatic
gradient is greatest (see congestive heart failure, Fig.
10-10).

Renal oedema is frequently found in loose tissues, such as the subcutaneous tissue around
the eyes (see Chapter 25).

Lymphatic oedema is
special form of oedema that can be congenital or acquired. A child born with
insufficient development of the lymphatic system will suffer from gradual
swelling of the affected body part as a result of accumulation of interstitial
fluid. Surgical destruction of lymphatic vessels can result in acquired,
lymphatic oedema (eg, following mastectomy).

Inflammative
processes, cancer cells or filarias (elephantiasis) also can obstruct
lymphatic vessels, so the limbs swell and become oedematous “elephant limbs.”

Thrombosis refers to a
condition with formation of multiple thrombi or clots within the vascular
system. The cause can be damage of the vessel wall, reduced bloodflow,
increased viscosity and hypercoagulability of the blood.

Embolismrefers
to the process through which a thrombus is dislodged from its attachment and
travels with the blood until it is lodged in a blood vessel too small to allow
its passage. The flowing blood carries emboli from thrombus material in the
deep pervic or leg veins to the lungs, where they block the bloodflow as
life-threatening pulmonary emboli.

Venous
thrombosis is is frequently related to peripheral artery disease or to
immobilisation. Bed rest or long immobilisation as during long flights can
result in deep venous thrombosis, presenting with pain in the calf and ankle
oedema. Anticoagulation therapy and elastic support stockings are used to
reduce the risk of pulmonary embolism.

The
bleeding disorders known as haemophilia are
relatively seldomly occurring, but vitamin K deficiency must be recognized as
a common and serious bleeding disorder, which can give rise to acute bleeding
anaemia (B1).

Haemophilia A is the
most frequent genetic disorder of
the intrinsic clotting system, characterised by a low coagulant concentration
of antihaemophilic factor (VIII). This
disorder is linked to the X-chromosome, and haemophilia affects only males,
who transfer the abnormal gene to their daughters, all of whom are carriers.
The female carrier of the abnormal gene is usually without symptoms and signs
of disease.

Haemophilia B(Christmas
disease, Factor IX deficiency) is not as common.

The activated partial thromboplastin time tests the competency of the slow intrinsic
clotting pathway. The contact factors are maximally activated by first mixing
citrate plasma with powdered glass. Then partial thromboplastins (V, cephalin,
and inosithin) are added. After addition of phospholipid and Ca2+,
the time it takes for coagulation to occur is measured. This is a preferential
test of the intrinsic clotting pathway, because factor III (tissue
thromboplastin from injured cells) is not available to trigger the extrinsic
clotting pathway (Fig. 8-6). Normal values are 35-45 s; the time is prolonged
in blood from patients with circulating anticoagulants. The time is also
prolonged in haemophilia and in other disorders with defective intrinsic
pathway factors.

Von Willebrands disease.
In most forms of Von Willebrands disease the plasma is deficient in both
factor VIII and Von Willebrands factor. The disease affects both sexes, which
is similar to mild haemophilia. The disorder is inherited as an autosomal dominant trait.The bleeding timetests the capacity of platelets to form plugs. A blood pressure cuff is
applied to maintain venous pressure at 5.3 kPa, and a standardised incision is
made on the volar surface of the forearm. Bleeding stops when a proper plug of
platelets has aggregated. The incision is blotted with filter paper at 30 s
intervals. The normal bleeding time is 4.5 min. The bleeding time is prolonged
to at least 10 min in Von Willebrands disease.

Aneurysms are abnormal
dilatations on a vessel typically due to degenerative processes in the wall.
Aneurysms on brain or coronary arteries may rupture (leading to sudden death),
because of their high lateral pressure (Eq. 8-2).

Aortic aneurysms are
usually due to arteriosclerosis with large atheromas in the wall. Aneurysms
are found as pulsatile dilatations of the abdominal or thoracic aorta (CT
scanning or ultrasound examination). Rupture of an aortic aneurysm presents as
shock with epigastric pain, and requires immediate surgery. Bleeding inside
the wall of the aorta obstructs the lumen (so-called dissecting aortic aneurysm), and also here emergency surgery is required.

Left ventricular aneurysm is a complication to ischaemic heart disease often diagnosed by
echocardiography (a case is drawn in Fig.10-8).

Saccular aneurysms are
found on the circle of Willis and its adjacent branches. Pulsations cause
pressure on surrounding structures, and spontaneous rupture often causes
sudden death.

Opening
and closure of cardiac valves is studied with echocardiography. This is a
versatile non-invasive technique used by cardiologists. When valvular diseases
cause the valves to open too little (stenosis)
or not close firmly enough (insufficiency),
the function of the heart is severely impaired.

·Bernoulli’s
equation(see Chapter 13) states that the total driving energy, applied to a continuously
flowing, small, ideal fluid volume (dV), which is flowing frictionless and laminar, equals the sum of 3
types of energy the kinetic energy (1/2 r v2- fluid density (r ) multiplied by the squared velocity) , the potential energy at the height (h)
and the gravity (G), and the laterally directed energy (ie, the lateral
pressure, P, directed towards the
walls).

The lateral pressure is
highest, where the velocity is lowest (eg, aneurysm ruptures). The equation of
continuity states that the velocity varies inversely with the cross-sectional
area of the tube. Consequently, the lateral pressure is highest where the
cross sectional area of the tube is largest.

Poiseuille´s
law: The volume rate (Vdot)
is equal to the driving pressure (DP)
divided by the resistance:V°= DP/Resistance.For the left ventricle, the bloodflow is actually cardiac output (Q°),
so the equation reads:

Doubling
the length of the system only doubles the resistance, but halving the radius
increases the resistance sixteen-fold. - Poiseuille´s
law is an approximation!

·Vascular Resistance
in parallel organs. In the systemic or
peripheral circulation the resistance in the single organs are mainly placed
in parallel, and the resistance of all organs (R1 toRn) are related to the
total (TPVR) by the following relation:

·Vascular resistance
in portal circulations. There are only a few serially connected elements (portal circulation): Spleen/liver, gut/liver,
pancreas/liver and hypothalamus/pituitary. For serial arranged resistance the
formula is:

A. Solutes
are exchanged in capillaries and small venules, because of the large surface
area and the thin endothelial vessel walls with many pores.

B.Oxygen diffuses from the blood to the interstitial fluid mainly across
the total surface of the endothelial cell walls.

C.Systemic oedema is caused by a small increase in mean arterial
pressure.

D.The bloodflow through the capillaries is regulated by arteriolar tone.

E. Oxygen is a water-soluble gas.

II. Each of the following five
statements have True/False options:

A. Oedema
is always caused by a hydrostatic pressure gradient, which is too great.

B. Macrocytic
anaemia without megaloblasts in the bone marrow is found in pregnancy, in
newborn babies, in hepatic disorders, in hypothyroidism and in aplastic
anaemia.

C. The
erythrocyte sedimentation rate is normally only a few mm per first hour, 15-20
with a common cold and 50-100 during pregnancy.

D. The reticulocyte count is normally less than 2.5% of the
red cell count, but following haemorrhage or haemolysis the relative number of
reticulocytes increases reflecting increased erythropoiesis.

E. The three-leaflet mitral valve prevents the leakage of
blood backward from the left ventricle to the left atrium.

III. Each of the following five
statements have True/False options:

A.The lack of vitamin B12 in the liver and the red
bone marrow inhibits the methyl-malonyl Co-A mutase and spoils the
purine-pyrimidine-DNA-synthesis. The inhibition of these two processes leads
to the neurological and the haematological disorders in pernicious anaemia.

D. Fenestrations are round windows found in the capillaries of
organs that transport lots of water (the bowels, glomerular capillaries of the
kidneys, pancreas and salivary glands). The protein lattice in the fenestrae
is so tight, that it keeps plasma proteins back.

E. Newtonian fluids are defined as fluids with a viscosity
that is dependent of the shear rate.

A grey-haired male with blue eyes, 52 years old, is
complaining of precordial pain, Dyspnoea upon stair climbing, and nausea. He
is depressed and suffers from frequent coughs.

The doctor observes icteric skin and eyes, ataxic
walking, dysdiadochokinesis, and positive Babinski. Massive subcutaneous
bleeding was found at the left hip.

Laboratory tests revealed the following abnormal
results:Lack of HCl in the
gastric fluid during fasting and following a pentagastrin test. Haematology
tests revealed large erythrocytes - many with nuclei. The red cell count was
1.4*1012 per l. The haematocrit was 0.21, and the blood
[haemoglobin] was 4 mM. The bleeding time was 90 min and the platelet count
was 50*109 per l. The concentration of vitamin B12 in
serum was 90 ng per l. The total [bilirubin] in serum was 18 mg per l, and the
rise mainly due to non-conjugated bilirubin. A test with radioactive B12 was specific for lackof intrinsic
factor production from the patient’s parietal cells.

1. What was the cause of this severe
pancytopenia (lack of all blood cell types)?

2. Calculate the oxygen capacity for
haemoglobin.

3. Why did the patient develop
leucopenia and thrombocytopenia? Was the lack of leucocytes and platelets of
any consequences to the patient?

In a healthy 20-year old male, with
a mean cardiac output of 7 l per min and a haematocrit of 45%, 20 l of fluid
are filtered per day in the capillaries. The concentration ofprotein in the fluid is 5 g per l.

A daily volume of 3 l of fluid passes into the
lymphatic vessels and is returned to the blood as lymphatic fluid. The
capillaries absorb the rest of the filtered fluid, supposedly together with a
small amount of protein (10 g).

The
total amount of plasma reaching the capillary system every day must be 55% of
all the whole
blood. Each day has 1440 min, so the plasma flow is: (7*1440*0.55) = 5544 l
per day.

·Haemopoiesis is the
formation of blood cells. All blood cells are derived from stem cells. Stem
cells produce erythroid cells, granulocytes, lymphoid cells, megacaryocytes
and monocytes by a number of differentiation steps. Stem cells maintain normal
cell populations in a healthy bone marrow controlled by haemopoietic growth
factors, and stem cells have the capacity for self-renewal.

·The erythropoiesis is
controlled by the hormone erythropoietin. Erythropoietin is liberated to the
circulating blood as a response to hypoxia of any cause (eg,
cardiac-pulmonary-renal disease).

·The successive change
in affinity during binding of the 4 oxygen molecules to each haemoglobin,
explains the sigmoid shape of the oxygen dissociation curve.

·When blood is
saturated under the normal ambient oxygen partial pressure (20 kPa or 150
mmHg), the oxygen capacity of haemoglobin is 1.34 and not the theoretical
maximum 1.39 ml STPD g-1.

·In many small vessels
bloodflow is non-Newtonian and Poiseuilles law is not applicable.

·Bloodflow tends to
become turbulent, when the flow velocity is high, the viscosity is low, and
the vessels are irregular.

·Starling’s
paracapillary circulation plays a dominating role in the transport of
crystalloids through the capillary wall.

·Of the daily
capillary filtration, 9/10 is reabsorbed in the venous end of the capillaries,
and 1/10 forms the lymph.

·Lymphatic fluids from
liver and kidney have a protein concentration equal to plasma’s, whereas
those from skin and skeletal muscles only contain 2% protein, and brain lymph
no protein at all.

·Severe anaemia
increases respiration, metabolic rate, and temperature due to the large
cardiac work.

·Aging and
arteriosclerosis increase the stiffness of elastic arteries, causing the
arterial compliance to fall from 1 to about 0.5 ml of blood per mmHg.

·Pernicious anaemia is
the most common cause of vitamin B12 (cobalamin) deficiency. This
is a disorder with an atrophic gastric mucosa. Parietal cell antibodies are
present in the plasma of 90% of all patients with pernicious anaemia. The
parietal cells of the gastric glands fail to secrete HCl and intrinsic factor.